DOCSLIB.ORG

Interventional Clinical Trial Results, and the Value of Genetic and Genomic

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Interventional Clinical Trial Results, and the Value of Genetic and Genomic Nutrigenomics NEW ZEALAND Interventional clinical trial results, and the value of genetic and genomic studies Lynnette Ferguson and Gareth Marlow, The University of Auckland Nutrigenomics or Nutrigenetics? Nutrigenetics Nutrigenomics What is Nutrigenetics? • The study of how individual genetic differences can affect the way we respond to nutrients in the foods we eat • The use of genetic characterisation in the the interpretation of clinical trial data In real terms LR Ferguson, 2012, Nature reviews Fat mass and obesity associated (FTO) 'Fatso' gene has clear link to obesity, say scientists NZ Herald 5:00AM Saturday April 14, 2007 Scientists have discovered the clearest link yet between genes and obesity in a study that opens the way to explaining why some people put on weight while others remain slim. The researchers have identified a genetic variation that gives a child a 70 per cent higher risk of developing obesity compared with a child who has not inherited the genetic variant. Tayside Schools Intensive phenotyping study Eating behaviour and food choice. Resting and total energy expenditure Courtesy of Colin Palmer N=100 FTO-targeted: Satiety-enhanced Foods The Development, Instrumental and Sensory Evaluation of a Gel-Based Model Food of Varying Textural Complexity. Danaé Larsen, Jingyuan Tang, Lynnette Ferguson, Marco Morgenstern and Bryony James Submitted Paper An eczema-related gene target of probiotics Differential modification of genetic susceptibility to childhood eczema by two probiotics Angharad R. Morgan, Dug Yeo Han, Kristin Wickens, Christine Barthow, Edwin A. Mitchell, Thorsten V. Stanley, James Dekker, Julian Crane and Lynnette R. Ferguson DOI: 10.1111/cea.12394 Just Published Unsuccessful Nutrigenetic Companies • Sciona Inc. was founded in 2000. • Provided gene-based personalised health and nutrition analysis and recommendations based on individual diet, lifestyle, and genetic profile. • It also offered genetic testing products, which addressed personal wellness, fitness, and nutritional issues. • Sciona Inc. went out of business in 2009. Unsuccessful Nutrigenetic Companies • MyGene specialised in the development of genetic tests and interpretive reports that assessed the genetic contribution of personal response to diet, also known as nutrigenetics. • In 2011 MyGene brought to market a nutrigenetic dietary program to optimise weight loss that was composed of a genetic test, a genetically allocated meal replacement formulation and 12- week dietary program (MyGene Weightloss Complete®). • Founded in 2007, the company has now been dissolved. Successful Nutrigenetic Companies International Science Advisory Board Nutrigenomix Inc. is a University Ben van Lynn Ahmed El- David of Toronto start-up biotechnology Ommen Ferguson Sohemy Jenkins company that moves genetic studies from the laboratory into the clinic. Working with our International Science Advisory Board, consisting of global leaders in the field of nutrigenomics, we have developed a panel of 7 genetic tests that enable your registered David Jose Bruce Bénédicte dietitian to provide you with Castle Ordovas German Fontaine-Bisson personalized nutritional recommendations based on your DNA. Nutrigenetics • Still viable, as a means of stratifying human populations for response to novel foods • BUT, single gene-functional food interactions are probably not of primary importance in all diseases. • May be more applicable to diseases such as IBD and metabolic syndrome • We have developed the appropriate methods, and could apply these where wanted So attention is turning to nutrigenomics: The study of how foods affect our genes Why Nutrigenomics? • To understand mechanisms whereby nutrition affects metabolic health • To optimise personal health/nutrition • To provide evidence for “functional food” health claims Two Strategies Afman & Muller J Am Diet Assoc 2006; 106:569-576 Will Nutrigenomics provide answers? You need to ask the right Questions Complex Nutrition + Complex Genotypes + Complex lifestyles + Omics Technologies Nutrigenomic Considerations? • Why do you need nutrigenomics? • What are the most suitable tools for your research and how to apply them? • What is healthy and how do you quantify? • What is the impact of nutrigenomics for the food industry? 1. In vitro studies e.g. Du Pont work on mechanism of action of a novel oil… Figure 1. Research Development Introduction Maturation Future Re-invent product in “4P” paradigm of “Personal Nutrition” Nutrigenomic Tool Kit • Transcriptomic profiling • Nuclear receptor profiling Decline • Lipidomics • Toxicogenomics • Genotyping Multi-level, multi-media, science-driven networking to engage thought-leaders and empowered consumers Return on Investment Investment on Return Research provides critical “Proof of Principle” underpinning product differentiation and patent estate to protect return on investment Time 2. In vivo studies Aim: validate use of nutrigenomics in small dietary intervention study • 30 healthy volunteers • Any gender, ethnicity, age, non-smokers • 6 week Mediterranean-style dietary intervention • 2 interventions; High or Low Traditional Biomarkers C-Reactive Protein Micronuclei Mean levels of C-reactive protein, Micronuclei scored in 1100 measured from serum samples of all cytokinesis-blocked cells for each subjects, before and after the dietary participant. Illustrated are the intervention. mean for each group. Transcriptomics • Input RNA required: 50–500 ng • Sensitivity: ≥1:100,000 • Detectable fold change: ≥2.0 fold • Dynamic range: ≥3log • Probe length: 25-mer • Probe Number: 530,000 • Transcripts: 36,000 • Represents: >20,000 genes Microarray Data How do we make sense of >30,000 data points? Statistical Pathway Heatmaps Analysis Analysis Statistical Analysis Raw Data: 30,000 transcripts Changed with inflammation: ~1,000 transcripts Non-hypothesis based study endpoint • Focus on those genes. • Search published literature, to learn about what they do in cells. • Put together a story that explains why they might be relevant to the change in diet. Differential Expression of top 150 Genes in High Intervention Diet (p<10-8) Week 1 Week 6 Pathways affected by dietary intervention Adding in metabolomics studies • To test for compliance • To discover biomarkers – Effects of foods on metabolism – Metabolite markers showing effects of foods on health Value of Nutrigenomics • Add to the understanding of the mechanism of nutrition • Aid in the development of personalised nutrition • Identify biomarkers and improve diagnostics for nutrition related diseases Value of Nutrigenomics to Industry • Support the development of functional foods – Demonstrate efficacy of the food-health claim in a cost-effective manner – Provide scientific validation for food health claims Nutrigenomics NEW ZEALAND Acknowledgements • Stephanie Ellett • Amalini Jesuthasan • Isobel Ferguson • Nishi Karunasinghe • William Zhu .
Load more

Recommended publications
  • Introduction to Nutrigenetics, Nutrigenomics and Epigenetics
    Medicine, Nursing and Health Sciences Introduction to Nutrigenetics, Nutrigenomics and Epigenetics Australia n China n India n Italy n Malaysia n South Africa Introduction to Nutrigenetics, Nutrigenomics and Epigenetics The Nutrition Society of Australia (Melbourne), Monash University and MyGene are pleased to invite you to our upcoming ‘Introduction to Nutrigenetics, Nutrigenomics and Epigenetics’ symposium. Please note, numbers will be capped at 100, and delegates need to sign up for their preferred workshop sessions using the link below. Where: Level 5 of The Alfred Centre, Monash University (Go to the 1.00pm Networking coffee/tea Foyer of Lecture Theatre ‘B’ set of lifts in the The Alfred Centre), 99 Commercial Road, 1.30pm Introduction to Nutrigenetics, Michael Fenech (CSIRO) Melbourne. Nutrigenomics and Epigenetics Jeff Craig (MCRI) When: 1-5.15pm, 2.30pm Global trends in genetics: research, Graeme Smith (MyGene) Tuesday 27 August 2013 technology and practice Melissa Adamski (MyGene) RSVP: Brianna McFarlane, [email protected] 3.10pm Tea/coffee break Foyer of Lecture Theatre (by 13 August 2013) 3.30pm Workshop 1 Level 5 breakout room The workshops are a choice of two 4.15pm Changeover time from following topics (click link below to sign up): 4.30pm Workshop 2 Level 5 breakout room Workshop preference: 5.15pm Close http://www.mygene.com.au/nsa- symposium/ 1. Designing genetic research projects (including considering the data, Biographies In 2003-05, Dr Fenech proposed a novel interpreting the data and validation) disease prevention strategy based on Michael Fenech 2. Adding genetic testing to your personalised diagnosis and prevention of current research project Professor Michael Fenech is recognised DNA damage by appropriate diet/life-style internationally for his research in nutritional intervention, which has led to the Genome 3.
    [Show full text]
  • 6615 Sofiva Genomics
    6615 SOFIVA GENOMICS Chairman Yi-Ning Su 2017.01.04 Company Profile SOFIVA GENOMICS Founded in July, 2012, SOFIVA GENOMICS focuses on clinical needs to develop next-generation testing models in genomic medicine Maternal-Fetal Medicine Genomic Medicine Clinical Medicine We have Asia’s leading genetic testing laboratory to provide comprehensive services to those in need Our Orientation ￭ Mothers and fetuses Targets ￭ Individuals with genetic diseases ￭ Individuals with cancer ￭ Healthy individuals ￭ Mothers and fetuses: Helping mothers successfully conceive and safely give birth to healthy babies ￭ Individuals with genetic diseases: Helping doctors in giving patients swift and accurate diagnoses and treatments Service Orientation ￭ Individuals with cancer: Facilitating the detection, prognosis, and tracking of cancer so that doctors can treat and monitor their patients more accurately ￭ Healthy individuals: Grasping their genetic health and risk of contracting disease and early planning for health promotion ￭ Now: Technology and platform combining biochemical detection + gene chip Technical + next-generation sequencing to provide customers with comprehensive Development testing services ￭Future: Development of comprehensive and customized testing using a single sample and a single platform ￭ Business promotion: Joint promotion and hospitals, introduction to medical personnel, onsite recommendations, promotion at foreign Marketing and domestic conferences/expos Channels ￭ PR promotion: online/Facebook marketing, literature and posters to
    [Show full text]
  • A Murine Atlas of Age-Related Changes in Intercellular Communication Inferred with the Package Scdiffcom
    bioRxiv preprint doi: https://doi.org/10.1101/2021.08.13.456238; this version posted August 15, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. scAgeCom: a murine atlas of age-related changes in intercellular communication inferred with the package scDiffCom Cyril Lagger 1,*, Eugen Ursu 2,*, Anaïs Equey 3, Roberto A. Avelar 1, Angela O. Pisco 4, Robi Tacutu 2, João Pedro de Magalhães 1,# 1. Integrative Genomics of Ageing Group, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK 2. Systems Biology of Aging Group, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania 3. Department of Medicine, Karolinska Institutet, Stockholm, Sweden 4. Chan Zuckerberg Biohub, San Francisco, California, USA *These authors contributed equally #Corresponding author’s email: [email protected] Abstract Dysregulation of intercellular communication is a well-established hallmark of aging. To better understand how this process contributes to the aging phenotype, we built scAgeCom, a comprehensive atlas presenting how cell-type to cell-type interactions vary with age in 23 mouse tissues. We first created an R package, scDiffCom, designed to perform differential intercellular communication analysis between two conditions of interest in any mouse or human single-cell RNA-seq dataset. The package relies on its own list of curated ligand-receptor interactions compiled from seven established studies. We applied this tool to single-cell transcriptomics data from the Tabula Muris Senis consortium and the Calico murine aging cell atlas.
    [Show full text]
  • Circulating Exosomes Potentiate Tumor Malignant Properties in a Mouse Model of Chronic Sleep Fragmentation
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 34 Research Paper Circulating exosomes potentiate tumor malignant properties in a mouse model of chronic sleep fragmentation Abdelnaby Khalyfa1, Isaac Almendros1,4, Alex Gileles-Hillel1, Mahzad Akbarpour1, Wojciech Trzepizur1, Babak Mokhlesi2, Lei Huang3, Jorge Andrade3, Ramon Farré4, David Gozal1 1Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL, USA 2Department of Medicine, Section of Pulmonary and Critical Care, Sleep Disorders Center, The University of Chicago, Chicago, IL, USA 3Center for Research Informatics, The University of Chicago, Chicago, IL, USA 4Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona-Institut Investigacions Biomediques August Pi Sunyer-CIBER Enfermedades Respiratorias, Barcelona, Spain Correspondence to: David Gozal, email: [email protected] Keywords: sleep fragmentation, obstructive sleep apnea, tumors, microenvironment, cancer biology Received: April 16, 2016 Accepted: June 30, 2016 Published: July 13, 2016 ABSTRACT Background: Chronic sleep fragmentation (SF) increases cancer aggressiveness in mice. Exosomes exhibit pleiotropic biological functions, including immune regulatory functions, antigen presentation, intracellular communication and inter- cellular transfer of RNA and proteins. We hypothesized that SF-induced alterations in biosynthesis and cargo of plasma exosomes may affect tumor cell properties. Results: SF-derived exosomes increased tumor cell proliferation (~13%), migration (~2.3-fold) and extravasation (~10%) when compared to exosomes from SC-exposed mice. Similarly, Pre exosomes from OSA patients significantly enhanced proliferation and migration of human adenocarcinoma cells compared to Post. SF- exosomal cargo revealed 3 discrete differentially expressed miRNAs, and exploration of potential mRNA targets in TC1 tumor cells uncovered 132 differentially expressed genes that encode for multiple cancer-related pathways.
    [Show full text]
  • Lifelong Restriction of Dietary Branched-Chain Amino Acids Has Sex-Specific Benefits for Frailty and Life Span in Mice
    ARTICLES https://doi.org/10.1038/s43587-020-00006-2 Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice Nicole E. Richardson 1,2,3, Elizabeth N. Konon1,2, Haley S. Schuster1,2, Alexis T. Mitchell1,2, Colin Boyle1,2, Allison C. Rodgers1, Megan Finke1,2, Lexington R. Haider1,2, Deyang Yu1,2, Victoria Flores1,2,4, Heidi H. Pak1,2,4, Soha Ahmad1,2, Sareyah Ahmed1,2, Abigail Radcliff1,2, Jessica Wu1,2, Elizabeth M. Williams1,2, Lovina Abdi1,2, Dawn S. Sherman1,2, Timothy A. Hacker1 and Dudley W. Lamming 1,2,3,4,5 ✉ Protein-restricted diets promote health and longevity in many species. While the precise components of a protein-restricted diet that mediate the beneficial effects to longevity have not been defined, we recently showed that many metabolic effects of protein restriction can be attributed to reduced dietary levels of the branched-chain amino acids (BCAAs) leucine, isoleucine and valine. Here, we demonstrate that restricting dietary BCAAs increases the survival of two different progeroid mouse mod- els, delays frailty and promotes the metabolic health of wild-type C57BL/6J mice when started in midlife, and leads to a 30% increase in life span and a reduction in frailty in male, but not female, wild-type mice when they undergo lifelong feeding. Our results demonstrate that restricting dietary BCAAs can increase health span and longevity in mice and suggest that reducing dietary BCAAs may hold potential as a translatable intervention to promote healthy aging. ietary interventions can robustly promote organismal both Drosophila and rodents5,19–22.
    [Show full text]
  • Dissecting the Genetic Etiology of Lupus at ETS1 Locus
    Dissecting the Genetic Etiology of Lupus at ETS1 Locus A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Immunobiology of the College of Medicine 2017 by Xiaoming Lu B.S. Sun Yat-sen University, P.R. China June 2011 Dissertation Committee: John B. Harley, MD, PhD Harinder Singh, PhD Leah C. Kottyan, PhD Matthew T. Weirauch, PhD Kasper Hoebe, PhD Lili Ding, PhD i Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease with strong evidence for genetics factor involvement. Genome-wide association studies have identified 84 risk loci associated with SLE. However, the specific genotype-dependent (allelic) molecular mechanisms connecting these lupus-genetic risk loci to immunological dysregulation are mostly still unidentified. ~ 90% of these loci contain variants that are non-coding, and are thus likely to act by impacting subtle, comparatively hard to predict mechanisms controlling gene expression. Here, we developed a strategic approach to prioritize non-coding variants, and screen them for their function. This approach involves computational prioritization using functional genomic databases followed by experimental analysis of differential binding of transcription factors (TFs) to risk and non-risk alleles. For both electrophoretic mobility shift assay (EMSA) and DNA affinity precipitation assay (DAPA) analysis of genetic variants, a synthetic DNA oligonucleotide (oligo) is used to identify factors in the nuclear lysate of disease or phenotype-relevant cells. This strategic approach was then used for investigating SLE association at ETS1 locus. Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry.
    [Show full text]
  • Critical Physiological and Pathological Functions of Forkhead Box O Tumor Suppressors
    DISCOVERIES (2013, Oct-Dec), 1(1): e5 DOI: 10.15190/d.2013.5 FOXO proteins control critical cellular decisions and cellular fate REVIEW Article Critical physiological and pathological functions of Forkhead Box O tumor suppressors Georgiana R. Dumitrascu1 and Octavian Bucur2,* 1“Victor Babes” National Institute of Pathology and Biomedical Sciences, Bucharest, Romania; 2Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA; Correspondence to: Dr. Octavian Bucur, Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA. Phone: +1 617 667 4314; E-mail: [email protected]. Citation: Dumitrascu GR, Bucur O. Critical physiological and pathological functions of Forkhead Box O tumor suppressors. Discoveries 2013, Oct-Dec; 1(1): e5. DOI: 10.15190/d.2013.5 ABSTRACT death (Puma); Bcl-2/adenovirus E1B 19 kDa-interacting The Forkhead box, subclass O (FOXO) proteins protein (bNIP3); PTEN – induced kinase 1 (Pink1); are critical transcription factors, ubiquitously peroxisome proliferative activated receptor-gama expressed in the human body. These proteins are (PGC1); glucose-6-phosphatase (G6Pase); phosphor- characterized by a remarkable functional diversity, enol-pyruvate carboxykinase (PEPCK); Agouti-related protein (Agrp); neuropeptide Y (NpY); pro-opiomelan- being involved in cell cycle arrest, apoptosis, ocortin (POMC); glycogenolytic gene glucose-6- oxidative detoxification, DNA damage repair, stem phosphatase (G6pc); manganese superoxide dismutase cell maintenance, cell differentiation, cell (MnSOD); CBP/p300-interacting trans-activator with metabolism, angiogenesis, cardiac development, ED-rich tail 2 (Cited 2); mixed lineage leukemia aging and others. In addition, FOXO have critical (MLL); L-selectin (CD62L); activation-induced cytidine implications in both normal and cancer stem cell deaminase (AID); biology.
    [Show full text]
  • Annual Scientific Meeting 23 – 27 March 2018, Adelaide Convention and Exhibition Centre
    Official Journal of the Asian Pacifi c Society of Respirology Respirology Volume 23 Supplement 1 March 2018 Annual Scientific Meeting 23 – 27 March 2018, Adelaide Convention and Exhibition Centre anzsrs Australian and New Zealand Society of Respiratory Science Ltd Volume 23 Supplement 1 March 2018 The Australia & New Zealand Society of Respiratory Science and The Thoracic Society of Australia and New Zealand (ANZSRS/TSANZ) Annual Scientifi c Meeting 23–27 March 2018 Adelaide, Australia Disclaimer This abstract book has been produced using author-supplied copy. Editing has been restricted to some corrections of spelling and style where appropriate. The publisher assumes no responsibility for any claims, instructions, methods or drug dosages contained in the abstracts. It is recommended that these are verifi ed independently. The contents contained herein are correct at the time of printing and may be subject to change. Contents ANZSRS Oral Abstracts New Investigators Awards (AO 001 – AO 005) ANZSRS Oral Abstracts Part (AO 006 – AO 012) ANZSRS Poster Abstracts ANZSRS Poster Abstracts (AP 001 – AP 016) TSANZ Oral Abstracts TSANZ Respiratory Nurses SIG Symposium 1 (TO 001 – TO 002) TSANZ Respiratory Nurses SIG Symposium 2 (TO 003 – TO 005) TSANZ Respiratory Nurses SIG Symposium 3 (TO 006 – TO 007) Asthma and Allergy 1 (TO 008 – TO 013) Paediatric (TO 014 – TO 019) Asthma and Allergy 2 (TO 020 – TO 025) Cystic Fibrosis 1 (TO 026 – TO 031) Occupational & Environmental Lung Disease / Population Health (TO 032 – TO 037) Primary Care/ Palliative
    [Show full text]
  • UCLA Electronic Theses and Dissertations
    UCLA UCLA Electronic Theses and Dissertations Title Expression of the Medial HOXA genes is indispensible for self-renewal in human hematopoietic stem cells Permalink https://escholarship.org/uc/item/2v95h1r0 Author Dou, Diana Remy Publication Date 2017 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA Los Angeles Expression of the Medial HOXA genes is indispensible for self-renewal in human hematopoietic stem cells A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Molecular Biology by Diana Remy Dou 2017 © Copyright by Diana Remy Dou 2017 ABSTRACT OF THE DISSERTATION Expression of the Medial HOXA genes is indispensible for self-renewal in human hematopoietic stem cells by Diana Remy Dou Doctor of Philosophy in Molecular Biology University of California, Los Angeles, 2017 Professor Hanna K.A. Mikkola, Chair Hematopoietic stem cells (HSCs) are able to self-renew, generate all lineages of the blood, reconstitute the hematopoietic system upon bone marrow (BM) transplantation, and thereby cure diseases of the blood and immune system. BM transplantations have successfully treated a wide range of blood-related diseases (i.e., β-thalassemia, leukemia, and HIV/AIDS). However, current demand for BM transplantations outstrips the quantity of HSCs available through cord blood banks and BM registries, and further requires finding matching HLA-types between patients and donors. Given these restrictions in quantity and compatibility, there is significant interest in developing alternative sources of transplantable HSCs by differentiating HSCs in vitro from pluripotent stem cells (PSCs), such as embryonic stem cells (ESCs).
    [Show full text]
  • Loss of Tip30 Accelerates Pancreatic Cancer Progression
    LOSS OF TIP30 ACCELERATES PANCREATIC CANCER PROGRESSION AND METASTASIS Imade E. Imasuen Williams Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the Department of Biochemistry and Molecular Biology, Indiana University July 2019 Accepted by the Graduate Faculty of Indiana University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Doctoral Committee ______________________________________ Thomas Hurley, Ph.D., Chair ______________________________________ Maureen Harrington, Ph.D. October 22, 2018 ______________________________________ Brittney-Shea Herbert, Ph.D. ______________________________________ Harikrishna Nakshatri, BVSc., Ph.D. ii © 2019 Imade E. Imasuen Williams iii DEDICATION I dedicate this dissertation to my late grandparents, Tamara and Mikhail Antonyuk, and my husband, Dwight Williams, as without them none of this would have been possible. iv ACKNOWLEDGEMENTS I would like to express my sincerest gratitude to my doctoral committee: Dr. Maureen Harrington, Dr. Brittney-Shea Herbert, Dr. Hari Nakshatri, and Dr. Thomas Hurley. Thank you for your scientific advisement, support, and guidance. Without your service I would not have made it this far. I would like to especially thank Dr. Thomas Hurley and Dr. Hari Nakshatri for co-advising me through the completion of my doctoral training and dissertation. I am also especially grateful for and am humbled by the entire committee’s dedication and feedback over the years, especially in regards to this dissertation and my grant writing. Your support and encouragement gave me an extraordinary amount of strength and courage. In addition to my committee, I would like to thank Dr. Francis Enane, Brandy Boyer- Wood (Indiana Biomedical Gateway (IBMG) Program for PhD Studies), Debra Barker (Indiana University Purdue-University of Indianapolis (IUPUI) Graduate Office), and Dr.
    [Show full text]
  • Linking Human-Genetic and Host-Microbiome Associations to Molecular Mechanisms Using Protein-Protein Interaction Networks
    LINKING HUMAN-GENETIC AND HOST-MICROBIOME ASSOCIATIONS TO MOLECULAR MECHANISMS USING PROTEIN-PROTEIN INTERACTION NETWORKS A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Juan Felipe Beltrán Lacouture December 2019 © 2019 Juan Felipe Beltrán Lacouture LINKING HUMAN-GENETIC AND HOST-MICROBIOME ASSOCIATIONS TO MOLECULAR MECHANISMS USING PROTEIN-PROTEIN INTERACTION NETWORKS Juan Felipe Beltrán Lacouture, Ph. D Cornell University 2019 We continue to better understand human disease through the study of human genetics and the human microbiome. Both fields use cohort study design, where the genes or microbiome communities of patients with a given condition are compared to a group of healthy controls. Systematically performing these comparisons to derive gene-disease associations and microbiome-disease associations is increasingly commonplace, but generating reasonable hypotheses for further study is still a challenge. Overcoming this challenge is vital to understand the causal molecular mechanisms of human disease. Quality-control and prioritization pipelines for human genetic variants from large-scale studies are hard to build, often involving several computational tools, databases, and tuning parameters. In Chapter 2, I present GeMSTONE, an online variant prioritization tool that allows researchers to leverage a large variety of resources to replicate and customize these pipelines without any computational experience or overhead. Understanding the location of disease-associated variants relative to protein interaction interfaces can help us understand whether they are likely to disrupt a protein interaction, thereby implicating a discrete molecular phenotype with the disease. In Chapter 3, I present Interactome INSIDER, an online resource that expands our network of protein interaction interfaces and performs widespread annotation of disease variants in this context.
    [Show full text]
  • Multivariate Analysis of Prokaryotic Amino Acid Usage Bias: a Computational Method for Understanding Protein Building Block Selection in Primitive Organisms
    Multivariate analysis of prokaryotic amino acid usage bias: a computational method for understanding protein building block selection in primitive organisms A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By DOUGLAS W. RAIFORD III B.S.C.S., Wright State University, 2002 2005 Wright State University COPYRIGHT BY Douglas W. Raiford III 2005 WRIGHT STATE UNIVERSITY SCHOOL OF GRADUATE STUDIES July 15, 2005 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPER- VISION BY Douglas W. Raiford III ENTITLED Multivariate analysis of prokaryotic amino acid usage bias: a computational method for understanding protein building block selection in primitive organisms BE ACCEPTED IN PARTIAL FULFILLMENT OF THE RE- QUIREMENTS FOR THE DEGREE OF Master of Science. Michael L. Raymer, Ph.D. Thesis Director Forouzan Golshani, Ph.D. Department Chair Committee on Final Examination Michael L. Raymer , Ph.D. Travis E. Doom , Ph.D. Dan E. Krane , Ph.D. Joseph F. Thomas, Jr. , Ph.D. Dean, School of Graduate Studies July 15, 2005 ABSTRACT Raiford III, Douglas . M.S., Department of Computer Science & Engineering, Wright State Uni- versity, 2005 . Multivariate analysis of prokaryotic amino acid usage bias: a computational method for understanding protein building block selection in primitive organisms. Organisms expend a significant fraction of their overall energy budget in the creation of proteins, particularly for those that are produced in large quantities. Recent research has demonstrated that genes encoding these proteins are shaped by natural selection to produce the proteins with low cost building blocks (amino acids) whenever possible. The negative correlation between protein production rate and their energetic costs has been established for two bacterial genomes: Escherichia coli and Bacillus subtilis.
    [Show full text]